Strategies for Dominant Diseases

Dominant diseases are caused by production of a gene product that is either insufficient (haploid insufficiency) or conducive to disease (dominant-negative effect). Theoretically, haploid insufficiency should be treatable by gene replacement therapy as outlined in the previous section for X-linked and recessive diseases. For dominant disorders produced by defective developmental genes, this correction would have to occur in early fetal development.

Disorders resulting from a dominant-negative effect require a different approach. Thus, strategies for treatment of dominant disease differ, depending on whether a functional gene product is produced. Some genes code for RNA molecules that can bind to mRNA from another gene and block the other molecule’s ability to be translated. Greater understanding of these genes may enable the creation of either drugs or new gene-encoded RNA molecules that can block the translation of mRNA for defective alleles, thus allowing only the normal allele to be expressed.

Another approach is the use of oligonucleotide or antisense DNA that are designed to bind with mRNA from mutant alleles, stopping the mRNA from being translated by ribosomes (Fig 5-10). Although many problems need to be resolved for such therapy to be effective, this approach holds promise for autosomal dominant disorders in which disease is caused by expression of the mutant gene product.

The use of ribozymes, RNA molecules that have the ability to cleave certain RNA molecules, provides another approach. A third method utilizes short interfering RNA (siRNA), also known as small interference RNA, to bind to mRNA and lead to the eventual degradation of specific mRNA molecules. The use of siRNA molecules as potential therapeutic agents has become increasingly popular, and this approach has proven to be a powerful means by which to study the function of novel gene products. However, one challenge with siRNA therapy is achieving intracellular delivery. Another challenge is cell-surface TLR3 receptor stimulation, which can induce immune or antiangiogenic processes as a generic class property.

Figure 5-10 Blockade of translation by antisense oligonucleotides. Normal gene transcription of DNA into mRNA is followed by translation of mRNA into protein. Antisense oligonucleotides complementary to a portion of mRNA bind mRNA, preventing translation—either by the steric effect of the binding process itself or (possibly) by inducing degradation of the mRNA by RNase.

(Reproduced with permission from Askari FK, McDonnell WM. Antisense-oligonucleotide therapy. N Engl J Med. 1996;334(5):316–318.)

A new form of genome editing known as CRISPR–Cas9 (clustered, regularly interspaced, short palindromic repeats–CRISPR-associated protein 9) has been used to correct point mutations in the DNA sequence of cells. Combining the technology of CRISPR–Cas9 with that of induced pluripotent stem cells (iPSCs) could potentially allow a scenario in which a skin biopsy is performed on a patient with an inherited retinal disease, skin cells are induced to produce pluripotent stem cells, and the causative mutation is edited out with CRISPR–Cas9. The cells could then be grown into the appropriate retinal cell line and implanted in the diseased eye. Before clinical trials commence, this personalized therapy, which would be costly, must still overcome issues with immunity and the risk of tumor development.

• Burnight ER, Gupta M, Wiley LA, et al. Using CRISPR-Cas9 to generate gene-corrected autologous iPSCs for the treatment of inherited retinal degeneration. Mol Ther. 2017; 25(9):1999–2013.

• Hung SSC, McCaughey T, Swann O, Pébay A, Hewitt AW. Genome engineering in ophthalmology: application of CRISPR/Cas to the treatment of eye disease. Prog Retin Eye Res. 2016;53:1–20.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.